Lipid and protein mediators of inflammation such as cytokines and chemokines have a profound impact on the formation and actions of each other (Serhan, C. N., J. Z. Haeggstrxc3x6m, and C. C. Leslie. 1996. Lipid mediator networks in cell signaling: update and impact of cytokines. FASEB J. 10:1147-1158). In particular, the cytokines TNFxcex1 and IL-1xcex2 play major roles in inflammation, septic shock and tissue injury. PMN perform a range of well-appreciated specialized functions, including chemotaxis, generation of reactive oxygen species and biosynthesis of potent lipid mediators (Weiss, S. J. 1989. Tissue destruction by neutrophils. N. Engl. J. Med. 320:365-376). In this regard, TNFxcex1 stimulates PMN to transcribe and release cytokines such as IL-1xcex2, enhances leukotriene biosynthesis, and up-regulates adhesion molecules (Marucha, P. T., R. A. Zeff, and D. L. Kreutzer. 1991. Cytokine-induced IL-1xcex2 gene expression in the human polymorphonuclear leukocyte: transcriptional and post-transcriptional regulation by tumor necrosis factor and IL-1. J. Immunol. 147:2603-2608). Since PMN represent approximately 70% of the peripheral blood leukocytes and are in many instances the initial cell type recruited to interstitial sites, they are now considered a significant source of xe2x80x9cproinflammatoryxe2x80x9d cytokines including TNFxcex1 and IL-1xcex2. These as well as other PMN-derived cytokines and chemokines can, in turn, affect the course of inflammatory and immune responses (Lloyd, A. R., and J. J. Oppenheim. 1992. Poly""s lament: the neglected role of the polymorphonuclear neutrophil in the afferent limb of the immune response. Immunology Today 13:169-172). In certain clinical settings, including respiratory distress syndrome, myocardial reperfusion injury, gout and rheumatoid arthritis, PMN contribute to ongoing damage of host tissues (Weiss, S. J. 1989. Tissue destruction by neutrophils. N. Engl. J. Med. 320:365-376; Hachicha, M., P. H. Naccache, and S. R. McColl. 1995. Inflammatory microcrystals differentially regulate the secretion of macrophage inflammatory protein-1 and interleukin-8 by human neutrophils: A possible mechanism of neutrophil recruitment to sites of inflammation in synovitis. J. Exp. Med. 182:2019-2025; Hansen, P. R. 1995. Role of neutrophils in myocardial ischemia and reperfusion. Circulation 91:1872-1885). Thus, it is of interest to understand the complex relationships between lipid mediators and TNFxcex1-evoked PMN responses in order to gain insight for new approaches in controlling these events.
The present invention pertains to methods for modulating a disease or condition associated with TNFxcex1 initiated polymorphoneutrophil (PMN) inflammation. The methods include administration to a subject, an effective anti-inflammatory amount of a lipoxin analog having the formula described infra, such that the TNFxcex1 initated PMN inflammation is modulated.
The present invention also pertains to methods for treating TNFxcex1 initiated polymorphoneutrophil (PMN) inflammation in a subject. The methods include administration of an effective anti-inflammatory amount of a lipoxin analog described infra, such that TNFxcex1 initiated polymorphoneutrophil (PMN) inflammation is treated.
The present invention further pertains to methods for modulating a disease or condition associated with TNFxcex1 initiated cytokine activity in a subject. The methods include, administration of an effective anti-TNFxcex1 amount of a lipoxin analog described infra, such that a disease or condition associated with TNFxcex1 initiated cytokine activity, is modulated.
The present invention further relates to methods for treating TNFxcex1 initiated cytokine activity in a subject. The methods include administration of an effective anti-TNFxcex1 amount of a lipoxin analog described infra, such that TNFxcex1 initiated cytokine activity, e.g., inflammation, is treated.
The present invention also relates to methods for modulating a disease or condition associated with TNFxcex1 initiated IL-1xcex2 activity in a subject. The methods include administration of an effective anti-inflammatory amount of a lipoxin analog described infra, such that a disease or condition associated with TNFxcex1 initiated IL-1xcex2, is modulated.
The present invention further pertains to methods for treating TNFxcex1 initiated IL-1xcex2 activity in a subject. The methods include administration of an effective anti-TNFxcex1 amount of a lipoxin analog described infra, such that TNFxcex1 initiated IL-1xcex2 activity, e.g., inflammation, is treated.
In preferred embodiments, the methods of the invention are performed in vitro or in vivo.
In another aspect, the present invention is directed to a packaged pharmaceutical composition for treating a the activity or conditions listed above in a subject. The packaged pharmaceutical composition includes a container holding a therapeutically effective amount of at least one lipoxin compound having one of the formulae described infra and instructions for using the lipoxin compound for treating the activity or condition in the subject.